Hereditary spherocytosis associated with deletion of human erythrocyte ankyrin gene on chromosome 8

HEREDITARY spherocytosis (HS) is one of the most common hereditary haemolytic anaemias¹. HS red cells from both autosound dominant and recessive variants are spectrin-deficient^2,3, which correlates with the severity of the disease³. Some patients with recessive HS have a mutation in the spectrin α-2 domain (S.L.M. et al., unpublished observations), and a few dominant HS patients have an unstable β-spectrin that is easily oxidized⁴, which damages the protein 4.1 binding site and weakens spectrin-actin interactions^5,6. In most patients, however, the cause of spectrin deficiency is unknown. The α- and β-spectrin loci are on chromosomes 1 and 14 respectively^7-9. The only other genetic locus for HS is SPH2, on the short arm of chromosome 8 (8p11)^10-14. This does not correspond to any of the known loci of genes for red cell membrane proteins including protein 4.1 (Ip36.2-p34)¹⁵, the anion exchange protein (AE1, band 3; 17q21-qter)^16,17, glycophorin C (2ql4-q21)¹⁸, and β-actin (7pter-q22)¹⁹. Human erthrocyte ankyrin, which links β-spectrin to the anion exchange protein, has recently been cloned^20,21. We now show that the ankyrin gene maps to chromosome 8pll.2, and that one copy is missing from DNA of two unrelated children with severe HS and heterozygous deletions of chromosome 8 (del(8Xpll-p21.1)). Affected red cells are also ankyrin-deficient. The data suggest that defects or deficiency or ankyrin are responsible for HS at the SPH2 locus.